The latest on our immune systems

Disclosure statement: Joanna Groom receives funding from the National Health and Medical Research Council, Australian Research Council and is a WEHI CSL Centenary Fellow.

This article is part of our occasional long read series Zoom Out, where authors explore key ideas in science and technology in the broader context of society and humanity.

Scientists love analogies. We use them continually to communicate our scientific approaches and discoveries.

As an immunologist, it strikes me that many of our recurring analogies for a healthy, functioning immune system promote excellent behaviour traits. In this regard, we should all aim to be a little more like the cells of our immune system and emulate these characteristics in our lives and workplaces.

Here are five life lessons from your immune system.

1. Build diverse and collaborative teams

Our adaptive immune system works in a very specific way to detect and eradicate infections and cancer. To function, it relies on effective team work.

At the centre of this immune system team sits dendritic cells. These are the sentinels and leaders of the immune system – akin to coaches, CEOs and directors.

They have usually traveled widely and have a lot of “life experience.” For a dendritic cell, this means they have detected a pathogen in the organs of the body. Perhaps they’ve come into contact with influenza virus in the lung, or encountered dengue fever virus in the skin following a mosquito bite.

After such an experience, dendritic cells make their way to their local lymph nodes – organs structured to facilitate immune cell collaboration and teamwork.

Here, like the best leaders, dendritic cells share their life experiences and provide vision and direction for their team (multiple other cell types). This gets the immune cell team activated and working together towards a shared goal – the eradication of the pathogen in question.

The most important aspect of the dendritic cell strategy is knowing the strength of combined diverse expertise. It is essential that immune team members come from diverse backgrounds to get the best results.

To do this, dendritic cells secrete small molecules known as chemokines. Chemokines facilitate good conversations between different types of immune cells, helping dendritic cells discuss their plans with the team. In immunology, we call this “recruitment.”

Much like our workplaces, diversity is key here. It’s fair to say, if dendritic cells only recruited more dendritic cells, our immune system would completely fail its job. Dendritic cells instead hire T cells (among others) and share the critical knowledge and strategy to steer effective action of immune cells.

T cells can then pass these plans down the line – either preparing themselves to act directly on the pathogen, or working alongside other cell types, such as B cells that make protective antibodies.

In this way, dendritic cells establish a rich and diverse team that works together to clear infections or cancer.

2. Learn through positive and negative feedback

Immune cells are excellent students.

During development, T cells mature in a way that depends on both positive and negative feedback. This occurs in the thymus, an organ found in the front of your chest and whose function was first discovered by Australian scientist Jacques Miller (awarded the 2018 Japan Prize for his discoveries).

As they mature, T cells are exposed to a process of trial and error, and take on board criticism and advice in equal measure, to ensure they are “trained” to respond appropriately to what they “see” (for example, molecules from your own body, or from a foreign pathogen) when they leave the thymus.

Importantly, this process is balanced, and T cells must receive both positive and negative feedback to mature appropriately – too much of either on its own is not enough.

In the diverse team of the immune system, cells can be both the student and the teacher. This occurs during immune responses with intense cross-talk between dendritic cells, T cells and B cells.

Our immune system knows that context is important – it doesn’t rely on a “one-size–fits-all” approach to resolve all infections.

This allows the cells of our immune system to perfectly respond to different types of pathogens: such as viruses, fungi, bacteria and helminths (worms).

In these different scenarios, even though the team members contributing to the response are the same (or similar), our immune system displays emotional intelligence and utilizes different tools and strategies depending on the different situations, or pathogens, it encounters.

Importantly, our immune system needs to carefully control attack responses to get rid of danger. Being too heavy handed leaves us with collateral tissue damage, such as is seen allergy and asthma. Conversely, weak responses lead to immunodeficiencies, chronic infection or cancer.

A major research aim for people working in immunology is to learn how to harness balanced and tailored immune responses for therapeutic benefit.

4. Focus on work/life balance

When we are overworked and poorly rested, we don’t function at our peak. The same is true for our immune cells.

An overworked immune cell is commonly referred to as being “chronically exhausted.” In this state, T cells are no longer effective at attacking tumour or virus-infected cells. They are lethargic and inefficient, much like us when we overdo it.

For T cells, this switch to exhaustion helps ensure a balanced response and avoids collateral damage. However, viruses and cancers exploit this weakness in immune responses by deliberately promoting exhaustion.

The rapidly advancing field of immunotherapy has tackled this limitation in our immune system head-on to create new cancer therapeutics. These therapies release cells of their exhaustion, refresh them, so they become effective once more.

This therapeutic avenue (called “immune checkpoint inhibition”) is like a self-care day spa for your T cells. It revives them, renewing their determination and efficiency.

This has revolutionized the way cancer is treated, leading to the award of the 2018 Nobel prize in Medicine to two of its pioneers, James P. Allison and Tasuku Honjo.

5. Learn from life experiences

The cornerstone of our adaptive immune system is the ability to remember our past infections. In doing so, it can respond faster and in a more targeted manner when we encounter the same pathogen multiple times.

Quite literally, if it doesn’t kill you, it makes your immune system stronger.

Vaccines exploit this modus operandi, providing immune cells with the memories without the risk of infection.

Work still remains to identify the pathways that optimize formation of memory cells that drive this response. Researchers aim to discover which memories are the most efficient, and how to make them target particularly recalcitrant infections, such as malaria, HIV-AIDS and seasonal influenza.

While life might not have the shortcuts provided by vaccines, certainly taking time to reflect and learn after challenges can allow us to find better, faster solutions to future problems.

The bugs we carry and how our immune system fights them

May 29, 2018

The immune system has to establish which cells belong to us and which are foreign, no mean feat.

Author: Peter C. Doherty is a Friend of The Conversation. Laureate Professor, The Peter Doherty Institute for Infection and Immunity

Disclosure statement: Peter C. Doherty is a Chief Investigator on an NHMRC Program grant focused on immunity to the influenza viruses. He chairs the board for the ARC Centre of Excellence for Convergent Bio-NanoScience and Technology, and is a member of advisory boards for Doctors for the Environment Australia, the Melbourne Sustainable Society Institute and the International One Health Initiative.

Human beings are large, complex, multicellular, multi-organ systems. We reproduce slowly and rely on a breadth of mechanisms that allow us to control the myriad of rapidly replicating, simple life forms that have evolved to live in or on us.

The system of defense is referred to collectively as immunity.

The word itself comes from the Latin immunis, describing the status of returned soldiers (Genio immunium) in the Roman state who were, for a time, exempt from paying taxes.

Our immunity protects us from many illnesses, including some forms of cancer. New cancer therapeutics, called immunotherapies, work by boosting our immune cells to fight cancer cells that have found ways to evade them.

The immune system is divided into two interactive spheres, the much older “innate” sphere, and the more recently evolved “adaptive” sphere. A primary challenge for the very specifically targeted cells that form the basis of adaptive immunity is to distinguish “self” (our own body cells and tissues) from “non-self” – the foreign invaders. When that goes wrong, we can develop autoimmune diseases such as multiple sclerosis or rheumatoid arthritis.

The organisms we carry around with us

The human body is host to many organisms over a lifetime. Some are dangerous to health (pathogens), some are benign, and some are necessary for proper functioning.

Most of the genetic material we carry around with us is “non-self”: principally harmless bacteria (called “commensals”) that live in the gastrointestinal tract.

Traditionally, studies focused on the “bad bugs” in our gut that cause diarrhoea and dysentery. But more recently, we’re learning there are also good guys. And there’s a general consensus we need to know more about the “microbiome”, the mass of bacteria in any “clinically normal” gut.

Gut bacteria provide essential vitamin B12 and when they die, release myriad proteins that will be broken down into amino acids, which the body needs. About 30% of our poo is comprised of dead bacteria.

Apart from our microbiome, normal human beings also have a substantial “virome.” Viruses differ from bacteria (which are cells in their own right) in that they are much simpler and can only replicate in living cells.

The greatest number of viruses we carry around are the “bacteriophages”, which infect the commensal bacteria in our gut. Not all “phages” are, however, benign. For example, the toxin that causes human diphtheria is encoded in the genome of a bacteriophage.

There’s also a spectrum of viruses that persistently infect our body tissues. The most familiar are herpes viruses, like those that cause cold sores (H. simplex) and shingles (H. zoster). Both viruses hide out in the nervous system and are normally under immune control. They re-emerge to cause problems as a consequence of tissue stress (such as a sunburnt lip) or as immunity declines with age (shingles). This is why a booster shingles vaccine is recommended for the elderly.

Our innate and adaptive immune systems

The innate system ranges from processes as basic as phagocytosis (ingestion of bacteria), to molecules like the interferons produced by any virus-infected cell that can limit replication. Such innate systems are found right across the evolutionary spectrum and don’t target specific pathogens.

The much younger adaptive immune system is what we stimulate with vaccines. A property of small white blood cells called lymphocytes, it divides broadly into two lineages: the B cells and T cells. These bear the extraordinarily diverse and very specific immunoglobulin (Ig) and T cell receptor (TCR) recognition molecules that detect invading pathogens (bacteria, virus, fungi and so on).

The immunoglobulins bind to “non-self” (foreign) proteins called “antigens”, while the T cell receptors are specifically targeted to “self” transplantation molecules.

The assassins of the immune system are then switched on; the killer T cells that eliminate virus-infected (or cancer) cells. Also activated are the “helper” T cells that secrete various molecules to “help” both the B cells and killer T cells differentiate and do their work.

How does our immune system learn and remember?

All lymphocyte responses work by massive cell division in the lymph nodes (the “glands” in our neck that swell when we get a sore throat). This process is started by small numbers of “naive” B and T cells that haven’t encountered the invader before, and only stops when the foreign invader is eliminated.

The B cells differentiate into large protein-secreting cells called plasma cells, which produce the protective antibodies (immunoglobulins) that circulate for years in our blood.

Most of the T cells die off after they’ve done their job, but some survive so they can remember how to target specific invaders. They can be rapidly recalled to their “killer” or “helper” function.

Prior infection or the administration of non-living or “attenuated” (to cause a very mild infection) vaccines sets up the memory so protective antibodies are immediately available to bind (and neutralise) pathogens like the polio or measles virus. While immune T cells are rapidly recalled to “assassin” status and eliminate pathogen-infected cells.

As you may have gathered from this very brief and far too simplified account, the immune system is extraordinarily complex. And it’s also very finely balanced with, for example, cross reactive responses to bacterial proteins sometimes setting us up for autoimmune diseases.

Another example of autoimmunity is rheumatoid arthritis, which can be triggered by blood-borne chemicals from tobacco smoke that modify “self” transplantation molecules in the joints.

And when we talk about the possible effects of the microbiome, or the “too clean” hypothesis, we’re discussing how exposure to bacteria and viruses can modify that immune balance in ways that directly affect our well-being. This is a very active area of research which, given the underlying complexity, presents scientists with big challenges as we seek to reach verifiable conclusions.